Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Applicant's preliminary amendment filed on April 17, 2026 is acknowledged. Claims 2-19, 21-23, 25, 27-38, 40-47, 49-55, 57, 58, 60, 61, 63, 64, 66-74, 76-78, 81, 83-88, 90-97, and 99-101 have been canceled. Claims 1, 20, 24, 26, 39, 48, 56, 59, 62, 65, 75, 79, 80, 82, 89, and 98 were amended. Claims 1, 20, 24, 26, 39, 48, 56, 59, 62, 65, 75, 79, 80, 82, 89, 98, and 102-107 are pending.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1, 19, 20, 24, 26, 39, 48, 56, 59, 62, 65, 75, 79, and 80) and the following species:
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in the reply filed on April 17, 2026 is acknowledged.
Claims 82, 89, and 98 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on April 17, 2026.
It is noted that newly added claims 102-107 are drawn to the dsRNA agent, or a salt thereof, of claim 1. Therefore, claims 102-107 will be examined with the elected invention.
Claims 1, 20, 24, 26, 39, 48, 56, 59, 62, 65, 75, 79, 80, and 102-107 are examined on the merits herein.
Priority
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Information Disclosure Statement
The information disclosure statement (IDS) submitted on April 17, 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings were received on September 7, 2023. These drawings are found acceptable by the examiner.
Specification
The substitute specification filed on December 18, 2023 has been entered.
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because the abstract contains the phrase “The disclosure relates” which can be implied. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Objections
Claims 1, 62, and 102 are objected to because of the following informalities:
Claim 1 recites in part “wherein the antisense strand…of SEQ ID NO: 37, and the antisense strand…of SEQ ID NO: 81”; however, according to the table on page 152 of the specification filed on December 18, 2023, SEQ ID NO: 37 refers to the sense sequence and SEQ ID NO: 81 refers to the antisense sequence of duplex AD-1191336.1. Therefore, claim 1 should read in part “wherein the sense strand…of SEQ ID NO: 37” (emphasis added).
Claim 62 recites in part “in the internal position(s) or the double stranded region”. It appears that there may be a typographical error and Applicant may have intended the word “of” instead of “or”.
Claim 102 recites in part “2-O-methyl (2-OMe)” and “2-fluoro (2-F)” and should recite “2’-O-methyl (2’-OMe)” and “2’-fluoro (2’-F)”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 80 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 80 recites the following:
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Claim 80 does not add anything additional to the product of claim 1; therefore, claim 80 fails to further limit the claim which it depends on.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claim 79 is rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101).
Claim 79 recites the following:
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The specification discloses methods of inhibiting expression of a GSK3α gene in a cell which includes contacting a cell with an RNAi agent, e.g., double stranded RNAi agent, in an amount effective to inhibit expression of GSK3α in the cell, thereby inhibiting expression of GSK3α in the cell [page 136, third full paragraph]. Contacting of a cell with a RNAi agent, e.g., a double stranded RNAi agent, may be done in vitro or in vivo. Contacting a cell in vivo with the RNAi agent includes contacting a cell or group of cells within a subject, e.g., a human subject, with the RNAi agent [page 136, last paragraph]. Thus, in view of the specification, the broadest reasonable interpretation of the claimed cell in claim 79 includes a human being. Therefore, the claim is directed to nonstatutory subject matter. It would be remedial to amend the claim to recite in part “An isolated cell” (emphasis added).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 20, 24, 26, 56, 79, and 80 are rejected under 35 U.S.C. 103 as being unpatentable over Sah et al. (US 9,029,525) as evidenced by Garcia et al. (Microbial Biotechnology 2012) in view of Aznarez et al. (US 11,096,956).
Regarding claims 1 and 20, Sah et al. teaches double-stranded ribonucleic acid (dsRNA) targeting Glycogen Synthase Kinase-3 (GSK-3) [abstract]. Sah et al. teaches that the dsRNA can include at least one modified nucleotide such as 2'-O-methyl and 2'-deoxy-2'-fluoro modified nucleotide [column 2, last paragraph]. Further, chemically linking one or more moieties or conjugates to the dsRNA enhances the activity, cellular distribution or cellular uptake of the dsRNA. Such moieties include but are not limited to lipid moieties such as a cholesterol moiety [column 14, lines 39-44]. Sah et al. teaches in Table 1 sequences of duplexes targeting mouse GSK3-alpha. The target sequence location identifies the target sequence in mouse GSK3-alpha mRNA NM_001031667.1, the unmodified sense strand is identical to the target sequence, and the unmodified antisense strand is complementary to the target sequence. Sah et al. SEQ ID NO: 5265 (designated as Db) is a sense strand and has a match to instant SEQ ID NO: 37 (designated as Qy) as shown in the alignment below.
Target Sequence
Location SID Unmodified sequence SID Modified sequence Strand
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758
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870
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Sah et al. SEQ ID NO: 5267 (designated as Db) is an antisense strand and has a match to instant SEQ ID NO: 81 (designated as Qy) as shown in the alignment below.
Target Sequence
Location SID Unmodified sequence SID Modified sequence Strand
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26
746
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Regarding claim 24, Sah et al. teaches that the dsRNA is chemically modified to enhance stability [column 11, last paragraph]. Sah et al. also teaches that preferred modified dsRNA backbones include phosphorothioates [column 12, first full paragraph].
Regarding claim 26, Sah et al. teaches that each strand of the dsRNA is generally between 15 and 30 nucleotides in length [column 9, fourth full paragraph].
Regarding claim 56, Garcia et al. teaches that cholesterol is a steroid, i.e. a class of terpenoid lipids, with a carbon skeleton virtually flat and relatively rigid formed by four fused alicyclic rings [page 679, left column, first paragraph]. Thus, as evidenced by Garcia et al., cholesterol is an alicyclic compound.
Regarding claim 79, Sah et al. teaches cells comprising the dsRNA [column 3, third full paragraph].
Regarding claim 80, Sah et al. teaches pharmaceutical compositions comprising a dsRNA and a pharmaceutically acceptable carrier [column 18, last paragraph].
However, Sah et al. does not teach that all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand comprise a nucleotide modification.
Aznarez et al. teaches that each monomer of the ASO is modified in the same way, for example each linkage of the backbone of the ASO comprises a phosphorothioate linkage or each ribose sugar moiety comprises a 2′O-methyl modification [column 118, last paragraph]. Aznarez et al. also teaches that any component of an ASO (e.g., a nucleobase, sugar moiety, backbone) may be modified in order to achieve desired properties or activities of the ASO or reduce undesired properties or activities of the ASO. For example, an ASO or one or more component of any ASO may be modified to enhance binding affinity to a target sequence on a pre-mRNA transcript; reduce binding to any non-target sequence; reduce degradation by cellular nucleases (i.e., RNase H); improve uptake of the ASO into a cell and/or into the nucleus of a cell; alter the pharmacokinetics or pharmacodynamics of the ASO; and modulate the half-life of the ASO [column 119, first full paragraph].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the dsRNA of Sah et al. wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand comprise a nucleotide modification because Sah et al. taught a double-stranded ribonucleic acid (dsRNA) targeting Glycogen Synthase Kinase-3 (GSK-3) and Aznarez et al. taught that each monomer of an antisense oligonucleotide is modified in the same way and any component of an ASO (e.g., a nucleobase, sugar moiety, backbone) may be modified to enhance binding affinity to a target sequence on a pre-mRNA transcript; reduce binding to any non-target sequence; reduce degradation by cellular nucleases (i.e., RNase H); improve uptake of the ASO into a cell and/or into the nucleus of a cell; alter the pharmacokinetics or pharmacodynamics of the ASO; and modulate the half-life of the ASO. One of ordinary skill in the art would have made such a modification because it would have amounted to combining known prior art elements to yield predictable results.
Claims 39, 48, 59, 62, and 65 are rejected under 35 U.S.C. 103 as being unpatentable over Sah et al. (US 9,029,525) as evidenced by Garcia et al. (Microbial Biotechnology 2012) in view of Aznarez et al. (US 11,096,956) as applied to claims 1, 20, 24, 26, 56, 79, and 80 above, and further in view of Nair et al. (WO 2019/217459).
Regarding claims 39, 48, 59, 62, and 65, the teachings of Sah et al. and Aznarez et al. are discussed above.
However, Sah et al. and Aznarez et al. do not teach that the lipophilic moiety is conjugated to one or more internal positions on at least one strand via a linker or carrier (claim 39). Further, Sah et al. and Aznarez et al. do not teach the range of internal positions on the sense and antisense strands (claim 48). Sah et al. and Aznarez et al. also do not teach that the lipophilic moiety contains a saturated or unsaturated C16 hydrocarbon chain (claim 59). Sah et al. and Aznarez et al. also do not teach that the lipophilic moiety is conjugated via a carrier that replaces one or more nucleotides in the internal position (claim 62) or conjugated to a nucleobase, a sugar moiety, or an internucleosidic linkage (claim 65).
Nair et al. teaches lipophilic moieties-conjugated double-stranded iRNAs at one or more internal positions on at least one strand capable of gene silencing [abstract]. Nair et al. teaches a double-stranded iRNA agent comprising: an antisense strand which is complementary to a target gene; a sense strand which is complementary to said antisense strand; and one or more lipophilic moieties conjugated to one or more internal positions on at least one strand, optionally via a linker or carrier [0006]. Further, one or more lipophilic moieties are conjugated to one or more of the following internal positions: positions 4-8 and 13-18 on the sense strand, and positions 6-10 and 15-18 on the antisense strand, counting from the 5’ end of each strand [0030]. Nair et al. also teaches that in one embodiment, the lipophilic moiety contains a saturated or unsaturated C16 hydrocarbon chain [0010]. In certain embodiments, the lipophilic moiety is conjugated to the double-stranded iRNA agent via a carrier that replaces one or more nucleotide(s) [0017]. Further, the lipophilic moiety is conjugated to a nucleobase, sugar moiety, or internucleosidic linkage of the double-stranded iRNA agent [0037].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the dsRNA of Sah et al. and Aznarez et al. wherein the lipophilic moiety is conjugated to one or more internal positions selected from positions 4-8 and 13-18 on the sense strand and positions 6-10 and 15-18 on the antisense strand via a linker or carrier, wherein the lipophilic moiety contains a saturated or unsaturated C16 hydrocarbon chain, wherein the lipophilic moiety is conjugated via a carrier that replaces one or more nucleotides in the internal position of the double stranded region, and wherein the lipophilic moiety is conjugated to a nucleobase, a sugar moiety, or an internucleosidic linkage because Sah et al. taught a double-stranded ribonucleic acid (dsRNA) targeting Glycogen Synthase Kinase-3 (GSK-3) and chemically linking one or more moieties or conjugates to the dsRNA such as lipid moieties, Aznarez et al. taught that each monomer of an antisense oligonucleotide is modified in the same way and a nucleobase may be modified in order to achieve or reduce desired properties or activities of the antisense oligonucleotide, and Nair et al. taught lipophilic moieties conjugated to double-stranded iRNAs at one or more internal positions capable of gene silencing. One of ordinary skill in the art would have made such a modification because it would have amounted to combining known prior art elements to yield predictable results.
Claim 75 is rejected under 35 U.S.C. 103 as being unpatentable over Sah et al. (US 9,029,525) as evidenced by Garcia et al. (Microbial Biotechnology 2012) in view of Aznarez et al. (US 11,096,956) as applied to claims 1, 20, 24, 26, 56, 79, and 80 above, and further in view of Parmar et al. (Chembiochem 2016).
Regarding claim 75, the teachings of Sah et al. and Aznarez et al. are discussed above.
However, Sah et al. and Aznarez et al. do not teach a phosphate mimic at the 5’-end of the antisense strand.
Parmar et al. teaches that incorporating 5’-(E)-vinyl-phosphonate, a metabolically stable phosphate mimic, to siRNA-GalNAc conjugates results in up to 20-fold improved in vitro potency and up to a threefold benefit in in vivo activity by promoting Ago2 loading and enhancing metabolic stability [abstract].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the dsRNA of Sah et al. and Aznarez et al. by incorporating a phosphate mimic at the 5’-end of the antisense strand because Sah et al. taught a double-stranded ribonucleic acid (dsRNA) targeting Glycogen Synthase Kinase-3 (GSK-3) and chemically linking one or more moieties or conjugates to the dsRNA such as lipid moieties, Aznarez et al. taught that each monomer of an antisense oligonucleotide is modified in the same way and a nucleobase may be modified in order to achieve or reduce desired properties or activities of the antisense oligonucleotide, and Parmar et al. taught that incorporating 5’-(E)-vinyl-phosphonate to siRNA-GalNAc conjugates results in up to 20-fold improved in vitro potency and up to a threefold benefit in in vivo activity. One of ordinary skill in the art would have made such a modification because it would have amounted to combining known prior art elements to yield predictable results.
Claims 102-107 are rejected under 35 U.S.C. 103 as being unpatentable over Sah et al. (US 9,029,525) as evidenced by Garcia et al. (Microbial Biotechnology 2012) in view of Aznarez et al. (US 11,096,956) as applied to claims 1, 20, 24, 26, 56, 79, and 80 above, and further in view of Nair et al. (WO 2019/217459).
Regarding claims 102-107, the teachings of Sah et al. and Aznarez et al. are discussed above. Sah et al. SEQ ID NO: 5266 (designated as Db) is a sense strand and has a match to instant SEQ ID NO: 233 (designated as Qy) as shown in the alignment below.
Target Sequence
Location SID Unmodified sequence SID Modified sequence Strand
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26
758
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140
566
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Sah et al. SEQ ID NO: 5268 (designated as Db) is an antisense strand and has a match to instant SEQ ID NO: 169 (designated as Qy) as shown in the alignment below.
Target Sequence
Location SID Unmodified sequence SID Modified sequence Strand
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26
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566
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Sah et al. teaches that the dsRNA includes two RNA strands that are sufficiently complementary to hybridize to form a duplex structure. One strand of the dsRNA (the antisense strand) includes a region of complementarity that is substantially complementary, and generally fully complementary, to a target sequence, derived from the sequence of an mRNA formed during the expression of the GSK-3 gene, the other strand (the sense strand) includes a region that is complementary to the antisense strand, such that the two strands hybridize and form a duplex structure when combined under suitable conditions. In one embodiment, the duplex is 21 base pairs in length [column 9, second full paragraph]. Sah et al. also teaches that each strand of the dsRNA is generally between 15 and 30, or between 18 and 25, or 18, 19, 20, 21, 22, 23, 24, or 25 nucleotides in length [column 9, fourth full paragraph]. Further, the dsRNA can include one or more single-stranded overhang(s) of one or more nucleotides, generally 1 or 2 nucleotides [column 9, fifth full paragraph]. Sah et al. teaches that the dsRNA is chemically modified to enhance stability [column 11, last paragraph]. Sah et al. also teaches that preferred modified dsRNA backbones include phosphorothioates [column 12, first full paragraph].
However, Sah et al. and Aznarez et al. do not teach a 2’-O-hexadecyl-cytidine-3’-phosphate or a vinyl-phosphonate modification. In addition, Sah et al. and Aznarez et al. do not teach the dsRNA agent design as recited in the claims.
Nair et al. teaches that the double-stranded iRNA agent further comprises a phosphate or phosphate mimic at the 5’-end of the antisense strand. In one embodiment, the phosphate mimic is a 5’-vinyl phosphonate (VP) [0038]. Nair et al. also teaches in Table 2 an example of a siRNA duplex wherein Uhd is a 2’-O-hexadecyl uridine (reproduced below):
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74
416
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[0845].
Although Sah et al. and Aznarez et al. do not teach the dsRNA agent design as recited in the claims, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to design a dsRNA agent according to the claims and arrive at the instantly recited SEQ ID NOS. using the design principles taught by Sah et al., Aznarez et al., and Nair et al. because it would have amounted to applying known design principles for a dsRNA to a GSK3-alpha mRNA sequence by known means to yield predictable results. The skilled artisan would have had a reasonable expectation of success in designing dsRNAs because as evidenced by Sah et al. it was well within the purview of the skilled artisan, and routine in the art to design dsRNAs that inhibit the target nucleic acid. One would have been motivated to modify the dsRNA of Sah et al. using the design principles of Sah et al., Aznarez et al., and Nair et al. to inhibit GSK-3 gene expression for the purposes of treating manic depression or other disorders caused by the expression of a GSK-3 gene as taught by Sah et al. and it would have amounted to combining known prior art elements to yield predictable results.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA TRAN whose telephone number is (571)270-0550. The examiner can normally be reached M-F 7:30 - 5:00pm.
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/C.T./
Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
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